Remote Monitoring App for Endocrine Therapy Adherence Among Patients With Early-Stage Breast Cancer

This randomized clinical trial assesses whether a remote monitoring app with or without additional weekly text messages improves adherence to adjuvant endocrine therapy compared with enhanced usual care among patients with early-stage breast cancer.


Introduction
Breast cancer is the most common cancer among women, and most women diagnosed have hormone receptor (HR)-positive tumors. 1 To reduce cancer recurrence risk and increase survival, treatment for HR-positive tumors typically includes long-term use of adjuvant endocrine therapy (AET) after primary treatment (ie, surgery, radiation, and/or chemotherapy). 2,3][6][7][8][9][10][11][12][13][14] Monitoring adverse symptoms and adherence with tailored education, especially between clinic visits, could help health care practitioners better manage AET-related symptoms and consequently improve long-term adherence and health outcomes.
7][18][19][20][21][22] Among these, a recent randomized clinical trial (RCT) of a text messaging intervention among women with early-stage breast cancer also failed to improve AET adherence, 21 highlighting the challenge of improving long-term AET adherence and the potential need for more personalized multilevel interventions.7][28] To our knowledge, no large RCTs with extended follow-up have evaluated tailored text messaging combined with remote monitoring for women with earlystage breast cancer receiving AET.
We evaluated a mobile app that captures weekly reported AET adherence and related symptoms with alerts to the oncology team and integration with the patient's electronic health records, with or without additional tailored text messages.Our study was a rigorous RCT to test the effectiveness of these interventions designed to improve patient-physician communication about AET adherence and related adverse symptoms.

Methods
We conducted a nonblinded RCT to test the effectiveness of a remote monitoring app with built-in alerts to the oncology team, with or without tailored text messages to participants, among women prescribed AET between November 15, 2018, and June 11, 2021. 29,30All procedures were approved by the University of Tennessee Health Science Center institutional review board.Eligible patients provided written consent in person before April 20 (prior to the COVID-19 pandemic) and electronic consent by email and signed using the REDCap eConsent framework after April 2020. 31The trial was

JAMA Network Open | Oncology
Endocrine Therapy Adherence App for Patients With Early-Stage Breast Cancer prospectively registered at ClinicalTrials.gov(NCT03592771).The trial protocol and statistical analysis plan have been described previously, 30 and the protocol is provided in Supplement 1.This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for RCTs. 32

Participants
Eligible participants were adult women with a diagnosis of ductal carcinoma in situ or stage I to III HR-positive breast cancer and a new prescription for AET, including aromatase inhibitors or tamoxifen, who were treated at a large community comprehensive oncology center serving western Tennessee, northern Mississippi, and eastern Arkansas, with a network of 14 clinic locations providing fully integrated, multidisciplinary cancer care.Eligible patients needed to have a mobile device with a data plan and an email address and be willing to use the electronic pillbox and complete brief surveys.Patients were excluded if they had previously used AET or had rheumatoid arthritis, fibromyalgia, or chronic pain disorder.We also excluded patients concurrently undergoing surgery or chemotherapy or who were unable to communicate in English.
Patients were identified using the electronic health record system and by physician referral.
Patients who consented and completed the enrollment survey were randomized using race-stratified (White or other race, based on what was entered in the medical record) block randomization with block size of 6 into 1 of 3 groups-app, app plus feedback, or enhanced usual care (EUC)-by the coordinator (A.N.C. randomized consented participants using REDCap).Race stratification was performed to ensure balance between groups.

Intervention EUC
All patients received education about AET and treatment-related symptoms.Patients were encouraged to have a follow-up appointment with their oncology team 8 to 12 weeks after initiating AET.At each clinic visit, patients were asked to complete an electronic tablet-based comprehensive symptom screening tool. 33,34Between visits, patients could report troublesome symptoms and receive support by calling the clinic.

App
In addition to EUC, app group participants received a weekly text message reminder to log into the study app to report adherence and any new or changing symptoms in the prior 7 days.The development process and app design have been described in prior publications. 29,30Responses that reached specific thresholds for adherence (3 or more missed doses in the past week) and symptoms (severity of 7 points or higher or increase of 4 points or more from last report, based on a 0-10 scale) triggered an alert to the oncology team.All responses entered in the app were integrated into the patient's electronic health record system in real time and available for review by the oncology team.

App Plus Feedback
In addition to the app, participants in the app plus feedback group received additional weekly tailored text messages, including educational information and encouragement related to AET adherence, AET-related symptoms, lifestyle, social support, and patient-physician communication.
Content was tailored to the participant's race and/or ethnicity, preferred activities and hobbies, sexual identity, and religion reported at enrollment and low-severity symptoms reported in the study app.

Data and Measures
At enrollment, participants self-reported sociodemographic characteristics, including race and ethnicity, educational level, household income, health literacy, and other patient-reported outcomes (described as follows). 35Race and ethnicity were ascertained by self-report.Race categories

JAMA Network Open | Oncology
Endocrine Therapy Adherence App for Patients With Early-Stage Breast Cancer included American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, or other (including multiracial), and ethnicity categories were Hispanic or not Hispanic.A 1-year survey was also collected to assess changes in patient-reported outcomes.
Adherence to AET was measured by an electronically monitored pillbox (Wisepill RT300, Wisepill Technologies) and by self-report in the 1-year follow-up survey.The pillbox used mobile telephone technology to wirelessly transmit data each time the device was opened 30 and was used by all participants for 1 year.From the pillbox data, we created an adherence measure of the proportion of days the participants took their medication according to the prescribed frequency over the 1-year follow-up period.Days hospitalized and prescriber-advised medication pauses were deducted from the denominator.Self-reported AET adherence was assessed with 5 questions regarding how often in the prior 6 months respondents missed an AET dose due to forgetfulness, carelessness, feeling better, feeling worse, or cost.Response options included often, sometimes, rarely, or never.We created a dichotomized indicator of higher AET adherence for those who responded never or rarely to all adherence questions.App use data were collected from an app data log for app and app plus feedback participants, including app logins and triggered alerts.App use was measured by the number of logins and the total number of triggered alerts among the app and app plus feedback groups during the 6-month intervention.
Symptom management activities were abstracted from patient medical records at 6 months.
They included actions by the oncology team to manage AET-related activities, such as temporary AET pauses, discontinuation, changes to a new AET, or a new prescription to manage an AET-related symptom.Participants were categorized as having symptom management if any of these changes were documented in their medical record during the 6-month intervention period.
Symptom burden was collected in the survey using the Functional Assessment of Cancer Therapy-Endocrine Symptoms. 36We used individual responses to 5-point Likert scales to calculate a composite score for symptom burden, with higher scores indicating lower symptom burden severity. 37lf-efficacy for managing symptoms was collected by survey using the validated 4-item Patient-Reported Outcomes Measurement Information System Self-Efficacy for Managing Symptoms short-form questionnaire.38 Participants indicated how confident they were in managing their symptoms on a 5-point scale.Scores ranged from 4 to 20, and higher scores indicate greater self-efficacy for managing symptoms.
Patient-physician communication was collected by survey using the 10-item Communication: Patient and Physician Peer Assessment. 39Responses were on a 5-point scale and were averaged over all 10 communication questions.
Quality of life was captured by survey with the 12-Item Short-Form Health Survey, 38,40 which consists of 12 items with physical component summary and mental component summary scores.The score range is 0 to 100, with higher scores indicating better quality of life.
Health care utilization was measured by survey using questions adapted from the National Health Interview Survey about the number of health care encounters in the prior 6 months, including office visits, ED visits, urgent care visits, and hospitalizations.Because ED visits, urgent care visits, and hospitalizations were relatively rare, we created a combined variable for these high-cost health care encounters.We also created a combined variable for all health care encounters.

Statistical Analysis
Using results from our group's pilot trial 41 and assuming 60% adherence in the EUC group, 75% adherence in the app group, and 85% adherence in the app plus feedback group, we had 95% power to detect a significant difference among the 3 study groups with 240 evaluable participants (80 per group) with a 5% type-1 error rate.We increased the sample size to 300 participants to account for attrition of up to 20%.For statistical analyses, we described participant characteristics by study group.Among those who completed the 1-year survey, the percentage of missing responses was less than 6.5% across outcomes.Following the intention-to-treat principle, we conducted multiple imputations with chained equations 42 for missing outcomes due to loss of follow-up or missing responses.Subsequent comparisons and regression results were generated based on the 25 imputed datasets.For AET adherence, we generated mean differences with 95% CIs in the pillbox-captured proportion of days adherent using ordinary least squares regression.Due to the skewed distribution, we also used the quantile regression to compare the median adherence by study arms.Self-reported high adherence was compared by study group using logistic regression.For outcomes measured at enrollment and follow-up, we examined the adjusted difference by study groups controlling for their baseline outcome value.We used ordinary least squares models for app use, app-triggered alerts, symptom burden, quality of life, self-efficacy for managing symptoms, and patient-physician communication

Results
We identified 313 eligible female patients; 9 (2.9%) declined to participate and 304 (97.1%) consented, completed the enrollment survey, and were randomized (104 to EUC, 98 to the app, and 102 to the app plus feedback).Seventeen patients (5.6%) withdrew or never completed any surveys before starting AET (Figure 1).Overall, 266 participants (87.5% of those randomized) completed the intervention and 1-year follow-up survey.

Sample Characteristics at Baseline
The mean (SD) participant age was 58.

App Use and Alerts
During the 6-month intervention, the mean number of logins was 18.9 (11.0) for app participants and

Health Care Utilization
Compared with EUC participants, after adjusting for baseline health care utilization levels, app participants did not have significantly fewer health care encounters over the previous 6 months

Symptom Burden, Quality of Life, Self-Efficacy, and Patient-Physician Communication
We did not find any statistically significant differences in changes over time by study group for symptom burden, quality-of-life scores, and patient-physician communication (Table 2 and eTables 1 and 2 in Supplement 2).

Symptom Management
During the 6-month intervention, a higher proportion of patients received symptom management in

Discussion
Among patients with early-stage breast cancer who were prescribed AET, an app-based intervention with weekly symptom and adherence monitoring and alerts to the care team, with or without tailored educational text messages, did not improve AET adherence.Nonetheless, with additional tailored messages, the remote monitoring intervention resulted in fewer high-cost health care encounters (ie, hospitalization, ED, and urgent care visits) without increasing the number of office visits compared with EUC.Although several studies have tested interventions aimed at improving AET adherence, a systematic review found that no prior large-scale behavioral interventions were associated with improved adherence with 1 year or longer follow-up. 44Similar to our group's pilot study, 41 a few studies have found short-term improvements in adherence. 22,28,45,46It is important to note that the adherence rate in the EUC group was higher than the expected rate used for sample size calculations, 30 which may have limited our ability to detect significant differences between groups.
It is possible that giving all participants the electronic pillbox with real-time remote monitoring, which we did not do in the pilot trial, may have increased adherence in the EUC group via the Hawthorne effect. 47Our findings highlight the difficulties of increasing long-term AET adherence and the need for novel multilevel sustained approaches that more effectively address adherence barriers.
It is notable that while decreasing the number of office visits, the app plus feedback intervention resulted in a decrease in the number of high-cost health care encounters compared with EUC.Moreover, more frequent remote symptom monitoring did not increase the number of office visits, and with additional tailored messages, it led to fewer office visits, although the P value did not reach the conservative Bonferroni adjusted threshold.App-only participants had consistent decreases in health care utilization compared with EUC participants, but these changes were  relatively smaller than those of the app plus feedback group and did not reach the threshold of statistical significance.While the magnitude of the reduction in high-cost encounters associated with the app plus feedback intervention may seem modest (0.40 fewer encounters), these events (hospitalizations, ED visits, and urgent care visits) are not common but are highly consequential for patients, health systems, and payers.Consistent with our results, a prior randomized trial of routine symptom monitoring during outpatient chemotherapy for various cancer types also found reductions in ED visits and hospitalizations. 249][50] Our study extends the prior evidence to show that remote symptom monitoring with additional tailored text messages led to fewer health care encounters, particularly high-cost encounters, without any detrimental impact on quality of life or increasing the number of clinic visits.These findings suggest that most symptoms triggering alerts were resolved with a simple call to a nurse, avoiding additional clinic visits or downstream costly health care encounters.
A possible mechanism for greater reductions in health care utilization among app plus feedback group compared to enhanced usual care may be more active symptom management by the oncology team from alerts and tailored educational messages.During the 6-month intervention, app plus feedback participants had fewer missed-dose alerts compared with app-only participants and more symptom-management changes by their oncology team compared with EUC participants.Our results showing fewer missed-dose alerts and more active symptom management among app plus feedback participants add to prior research showing that tailored messaging combined with remote monitoring was associated with improved care engagement and self-management for patients with early-stage breast cancer. 26,27

Strengths and Limitations
This trial had many strengths, including a rigorous randomized study design, racially and economically diverse participants, and 2 measures of medication adherence-electronically monitored and selfreported.Our study also has some limitations.Patients were recruited from a single large, comprehensive cancer center that had already been routinely monitoring patient-reported symptoms at every clinic visit; therefore, our results may not be generalizable to other care settings.For example, we did not detect statistically significant changes in patient-physician communication, self-efficacy for managing symptoms, or quality-of-life composite scores, which were high at enrollment, from the app and app

Figure 2 . 1 -B
Figure 2. 1-Year Adjuvant Endocrine Therapy Adherence Between Intervention Groups Endocrine Therapy Adherence App for Patients With Early-Stage Breast Cancer JAMA Network Open.2024;7(6):e2417873.doi:10.1001/jamanetworkopen.2024.17873(Reprinted) June 27, 2024 4/13 Downloaded from jamanetwork.comby guest on 07/01/2024 . A zero-inflated model was used for health care utilization outcomes due to excessive zeros; zeroinflated Poisson regression was used unless overdispersion was detected, in which case, zeroinflated negative binomial regression was used instead.Sensitivity analyses were conducted among participants who were randomized and completed the 1-year follow-up survey without imputation; the results are provided in eTable 1 in Supplement 2. All data management and analyses were conducted using SAS, version 9.4 (SAS Institute Inc), and Stata, release 16 (StataCorp LLC).Statistical significance was determined using 2-sided tests.Results adjusting for multiple testing with 10 study outcomes (pillbox-monitored adherence, self-reported high adherence, symptom burden, physical health quality of life, mental health quality of life, self-efficacy for managing symptoms, patientphysician communication, office visits, high-cost health care encounters, and all health care encounters) using the conservative Bonferroni adjustment at P < .005weremostly consistent with the findings using a significance threshold of P < .05.43 6%) as Black or African American, 192 (63.2%) as White, and 4 (1.3%) as multiracial.Nine participants (3.0%) identified as Hispanic ethnicity.Sixty-five (21.4%) had an income below 200% of the federal poverty level, and 60 (19.7%) had an educational level of high school diploma or lower 6 (10.8) years; the median age was 60 years (range, 31-83 years).One participant (0.3%) identified as American Indian or Alaska Native, 5 (1.6%) as Asian, 102(33.(Table1).

Table 1 .
Baseline Characteristics a Data are presented as the No. (%) of participants unless otherwise indicated.b c Rural-urban commuting area (RUCA) codes were used to categorize residential location as urban if RUCA was 1 and rural or suburban if RUCA was 2 to 10.

Table 2 .
Adjusted Changes in Secondary Outcomes From Baseline to 1-Year Follow-Up for Intervention Groups Compared With Enhanced Usual Care a c P < .05. b High-cost encounters included emergency department visits, urgent care visits, and hospitalizations.
The intervention period was relatively short, only 6 months, for a medication that is usually recommended to continue for 5 or more years.Our recruitment period spanned the start of the COVID-19 pandemic, which caused significant disruptions in care, including fewer in-person visits.51Nonetheless,suchdisruptionsshould be similar across study groups, so differences observed by study groups may be attributable to the randomized intervention.Last, we did not collect data on the reason for each health care encounter or whether encounters were related to the patient's cancer diagnosis or AET use.In future analyses, we plan to evaluate potentially differential effects among subgroups, such as those with lower health literacy or younger ages.GraetzI, McKillop CN, Stepanski E, Vidal GA, Anderson JN, Schwartzberg LS.Use of a web-based app to improve breast cancer symptom management and adherence for aromatase inhibitors: a randomized controlled feasibility trial.J Cancer Surviv.2018;12(4):431-440.doi:10.1007/s11764-018-0682-z42.van Buuren S, Boshuizen HC, Knook DL.Multiple imputation of missing blood pressure covariates in survival analysis.Stat Med.1999;18(6):681-694.doi:10.1002/(SICI)1097-0258(19990330)18:6<681::AID-SIM71>3.0.CO;2-R 43.Perneger TV.What's wrong with Bonferroni adjustments.BMJ.1998;316(7139):1236-1238.doi:10.1136/bmj.316.7139.123644.Hurtado-de-Mendoza A, Cabling ML, Lobo T, Dash C, Sheppard VB.Behavioral interventions to enhance adherence to hormone therapy in breast cancer survivors: a systematic literature review.Clin Breast Cancer.2016; 16(4):247-255.e3.doi:10.1016/j.clbc.2016.03.006 45.Arch JJ, Crespi CM, Levin ME, et al.Randomized controlled pilot trial of a low-touch remotely-delivered values intervention to promote adherence to adjuvant endocrine therapy among breast cancer survivors.Ann Behav Med.2022;56(8):856-871.doi:10.1093/abm/kaab11846. Park HR, Kang HS, Kim SH, Singh-Carlson S. Effect of a smart pill bottle reminder intervention on medication adherence, self-efficacy, and depression in breast cancer survivors.Cancer Nurs.2022;45(6):E874-E882. doi:10.1097/NCC.000000000000103047.McCarney R, Warner J, Iliffe S, van Haselen R, Griffin M, Fisher P. The Hawthorne effect: a randomised, controlled trial.BMC Med Res Methodol.2007;7:30.doi:10.1186/1471-2288-7-3048.Krzyzanowska MK, Julian JA, Gu CS, et al.Remote, proactive, telephone based management of toxicity in outpatients during adjuvant or neoadjuvant chemotherapy for early stage breast cancer: pragmatic, cluster randomised trial.BMJ.2021;375:e066588.doi:10.1136/bmj-2021-06658849.Absolom K, Warrington L, Hudson E, et al.Phase III randomized controlled trial of eRAPID: eHealth Intervention During Chemotherapy.J Clin Oncol.2021;39(7):734-747.doi:10.1200/JCO.20.0201550.Wheelock AE, Bock MA, Martin EL, et al.SIS.NET: a randomized controlled trial evaluating a web-based system for symptom management after treatment of breast cancer.Cancer.2015;121(6):893-899. doi:10.1002/cncr.2908851.Paladino AJ, Pebley K, Kocak M, et al.An examination of health care utilization during the COVID-19 pandemic among women with early-stage hormone receptor-positive breast cancer.BMC Health Serv Res.2022;22 (1):1403.doi:10.1186/s12913-022-08705-9App Use and Alerts During the 6-Month Intervention Among App and App Plus Feedback Participants eTable 1. Adjusted 1-Year AET Adherence and Changes in Secondary Outcomes from Baseline to 1-Year Follow-Up for Intervention Groups Compared With Enhance Usual Care Without Imputation eTable 2. Descriptive Outcomes at Enrollment and 1-Year Follow-Up by Randomization Arm With and Without Imputation for Missing Outcomes plus feedback interventions.It is possible that other care settings that do not already routinely monitor patient-reported symptoms would have more room for improvement and could experience different results.We limited recruitment to only English-speaking patients with access to an internet-connected computer or smartphone; future research should explore providing symptom monitoring in multiple languages as well as investigate solutions for individuals who do not have technology access.41.